INTRODUCTION:
The oral route of drug delivery is typically considered the favored and the most user-friendly means of drug administration having the highest degree of safety and patient compliance. Hence, several efforts are aimed to identify orally active candidates that would provide reproducible and effective plasma concentrations in vivo1. Recently, drug delivery systems have focused on constant/sustained drug output with the objective of minimizing peaks and valleys of drug concentrations in the body to optimize drug efficacy and to reduce adverse effects. A reduced dosing frequency and improved patient compliance can also be expected for the controlled/sustained release drug delivery systems, compared to immediate release preparations2. However, in the field of modern drug therapy, growing attention has been focused on Chronopharmaceutic drug delivery systems (ChDDs) for which conventional controlled drug-release systems with a continuous release are not ideal.
ChDDs are obtained from the concepts of chronobiology and pharmaceutics. Chronobiology is a self-sustaining oscillations of endogenous origin defined by the characteristics of period, level, amplitude and phase3. It can also be termed the study of biological rhythms and their mechanisms4. Pharmaceutics is an area of biomedical and pharmaceutical sciences that deals with the design and evaluation of pharmaceutical dosage forms to assure their safety, effectiveness, quality and reliability. Hence, chronopharmaceutics can be defined as a branch of pharmaceutics devoted to the design and evaluation of drug delivery systems that release a bioactive agent at a rhythm that ideally matches the biological requirement of a given disease therapy. Ideally, ChDDs should embody time-controlled and site-specific drug delivery systems5. Based on the route of administration ChDDs are classified into three, which include oral, parenteral and transdermal. However, this review focused on the oral routes of ChDDs. Some advantages of ChDDs include reduced dosing frequency, enhanced compliance and convenience, reduced toxicity, instantaneous drug level matching exact biological and physiological needs to treat the disease at each point in time, drug effect matching body need to treat diseases, and also decreased total required therapeutic dose. However, some drawbacks of this system include delayed attainment of pharmacodynamic effect, unpredictable bioavailability, enhanced first-pass hepatic metabolism when compared to the parenteral route, dosing inflexibility, and increased cost (compared to conventional dosage forms).
History of ChDDs - Is it new?
Previously, it has been observed that daily rhythms occurs in plants and animals However, during the 4th century BC, Alexander the Great’s noted that the leaves of certain trees opened during the day and closed at night showing a clear rhythmicity. In 17th century, the French astronomer Jean Jacques d’Ortous deMairan conducted the first experiment on biological rhythms6. Adkisson in 1966, observed that insects use photoperiodic information to bring their growth and also during the periods of latent season7. Circadian rhythms of behaviour in mammals have been observed to be robust and precise8,9. Chronopharmacology got developed into a scientific domain during the early 70’s. It investigates the effect of drugs as a function of biological time on 24 hr scale. However, this can be understood by three concepts. Firstly, the Chronokinetics which refers to rhythmic changes in bioavailability, absorption, distribution, metabolism and excretion of the drug, secondly, chronesthesy this relates to rhythmic changes of target biosystem to drug and finally chronergy which refers to the rhythmic changes in integrated overall effects of drugs. The term ‘‘circadian’’ was coined by Franz Halberg from the Latin circa, meaning about, and dies, meaning day10. Oscillations of shorter duration are termed ultradian i.e. more than one cycle per 24 h while oscillations longer than 24 h are called infradian i.e. less than one cycle per 24 h rhythms. Ultradian, circadian, and infradian rhythms coexist at all levels of biologic organization4.
Diseases currently on target for chronopharmaceutical formulations
All functions in human are highly organized in time as biological rhythms of diverse periods, both in health and disease conditions. This represents a challenge for those involved in the development of drug-delivery systems to make possible the treatment of illness according to these physiological rhythms as a means of improving therapeutic outcomes. Some diseases currently on target for chronopharmaceutical formulations include:
It has been demonstrated that airway resistance increase progressively at night in asthmatic patients11. Since bronchoconstriction and excacerbation of symptoms vary during the day, asthma is well suited for chronotherapy, namely with methylxanthine (theophylline), beta 2- agonists (salbutamol) etc. Circadian changes in the physiology of the lungs of asthmatic patients results in an increase in diurnal resistance causing dyspnea. It has been estimated that symptoms of asthma occur 50 to 100 times more between 3.0 am and 5.0 am12-15.
Allergic rhinitis:
Allergic rhinitis is highly prevalent affecting about 25% and 40% of adults and children in USA respectively16. The most common symptoms include sneezing, runny nose, nasal pruritis and nasal congestion. The nasal congestion and obstruction are usually worse during the night hours; hence this can sometimes disrupts sleep. This results in daytime fatigue, poor work and school performance16. In mid 19th century Trousseau was one of first clinical scientists to recognize and emphasize the prominence of day to night pattern in AR symptoms; his observations on their clock-time distribution, in particular their worsening during the nighttime, led him to describe AR as “L'asthme dunez”, (in English: “asthma of the nose”16.
Rheumatoid arthritis:
Rheumatoid arthritis (RA) varies within a day and between days in a circadian manner and the daily morning stiffness that is observed in RA patients has become one of the diagnostic criteria of the disease17. Human pro-inflammatory cytokine production exhibits a diurnal rhythmicity with peak levels during the night and early morning, at a time when plasma cortisol (anti-inflammatory) is lowest and melatonin (pro-inflammatory) is highest18. Previously, some workers have shown that some NSAIDs, such as indomethacin and Ketoprofen have better morning absorption with greater rate and/or extent of bioavailability when their controlled release formulations are given in the morning than when they are given in the evening19-20
It is well known that patients with peptic ulcer disease normally experience maximal acid secretion and pain near the time they go to bed, since the rate of stomach acid secretion is highest at night21. Hence, most ulcer medications are administered at night to enhanced therapeutic effect.
Myocardial Infarction:
The onset of myocardial infarction has been shown to be more frequent in the morning with 35% events occurring between 6 am and noon. Acute cardiac arrest and transient myocardial ischemia show an increased frequency in morning. It may also be important to recognize that the risk of heart attack appears to be greatest during the early morning hours after awakening. The causes for these findings have been suggested to be release of catecholamines, cortisol, increase in the platelet aggregation and vascular tone22
Hypertension:
The role of chronotherapeutics in hypertension management is based on the recognition that blood pressure does not remain constant during the day, tending to be higher in the early morning and lower in the evening. This seems to be related to the maximum propensity in the morning and minimum after wakening up period. Wake propensity is mediated through factors such as increase in body temperature, respiration, cortisol and adrenaline levels. These factors have obvious effects on heart rate and blood pressure. This documented rise in blood pressure near the time of awakening is responsible in significant part for the increase of cardiovascular risk in the morning23.
The initial goal of treatment of hypertension was to lower blood pressure by a uniform amount throughout the entire day. Chronopharmaceutics address this limitation by delivering drug in concentration that vary according to the body’s circadian rhythms. In this way, it is possible to reduce blood pressure at the times where patients are at highest risk for cardiovascular events without excessive reduction during low periods. Presently, there are some novel antihypertensive drug delivery products in the market that release drug during the vulnerable period of 6 am to noon upon administration of the medications at 10 pm. Some examples include Innopran XL (Propanolol) and Cardizem LA (Diltiazem) these are manufactured by GlaxoSmithKline USA and Biovail Corporation Mississauga, Canada respectively23.
Diabetes:
The circadian variations of glucose and insulin in diabetes have been extensively studied and their clinical importance in case of insulin substitution in type 1 diabetes has been previously discussed24-29. The goal of insulin therapy is to mimic the normal physiologic pattern of endogenous insulin secretion in healthy individuals, with continuous basal secretion as well as meal-stimulated secretion. Providing basal insulin exogenously to patients with diabetes inhibits hepatic glucose production30. Exogenous administration of mealtime doses promotes peripheral glucose uptake as well as reducing hepatic glucose release30.
Neurological disorders:
As an integrative discipline in physiology and medical research, chronobiology renders possible the discovery of new regulation processes regarding the central mechanisms of epilepsy. Chronophysiology investigations considered at a rhythmometric level of resolution suggest several heuristic perspectives regarding the central pathophysiology of epilepsy and the behavioural classification of convulsive events. Such circadian studies also show that chronobiology raises some working hypotheses in psychophysiology and permits the development of new theoretical concepts in the field of neurological science31, 32. It is also well known that the brain area with the highest concentration in noradrenergic nerve terminals and noradrenaline (NA) have a circadian rhythm in their content of NA33. Moreover, it has been shown that the human sleep, its duration and organization depend on its circadian phase34. A breakthrough chronopharmaceutical formulation against insomnia that plagues many people would be the one that addresses the entire oscillatory cycle of human sleeping process.
Technologies in ChDDs:
Diffucaps ® technology: This is a capsular unit dosage form, which delivers drug into the body in a circadian release fashion. It comprises one or more drug particles (beads, pellets, granules, etc.). Each bead population exhibits a pre-designed rapid or sustained release profile with or without a predetermined time lag of 3–5 hours. The active core of the dosage form may comprise an inert particle or an acidic or alkaline buffer crystal (e.g., cellulose ethers), which is coated with an Active Pharmaceutical Ingredient (API) - containing film-forming formulation and preferably a water soluble film forming composition e.g. poly vinyl pyrrolidine (PVP), hydroxyl propyl methyl cellulose (HPMC), to form a water-soluble/dispersible particle35,36. The active core may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing the API. Such ChDDs is designed to provide a plasma concentration–time profile that varies according to physiological need during the day, that is, mimicking the CR and severity/manifestation of a cardiovascular disease, predicted based on pharmacokinetic and pharmacodynamic considerations and in vitro/in vivo correlations35.
ChronsetTM technology: It is a proprietary OROS® delivery system that reproducibly delivers a bolus drug dose >80% drug release within 15 minutes, in a time- or site-specific manner to the gastrointestinal tract (GIT). In this technology, the drug formulation is protected from chemical and enzymatic degradation in the GIT before release, hence, the timing of release is unaffected by GIT contents. The drug release onset times varying from 1 to 20 hours can be achieved by balancing the semi permeable membrane, the osmotic engine and the other attributes of the system configuration35.
CeformTM technology: This allows the production of uniformly sized and shaped microspheres of pharmaceutical compounds. This approach is based on ‘‘melt spinning’’, which means subjecting solid feedstock (i.e., biodegradable polymer/bioactive agent combinations) to a combination of temperature, thermal gradients, mechanical forces, flow, and flow rates during processing. The microspheres obtained are almost perfectly spherical, having a diameter that is typically 150–180 mm, and allow for high drug content35, 37. The microspheres can be used in a wide variety of dosage forms, including tablets, capsules, suspensions, effervescent tablets, and sachets. The microspheres may be coated for controlled release with an enteric coating or may be combined into a fast/slow release combination37.
Egalet® technology: This offers a delayed release form consisting of an impermeable shell with two lag plugs, enclosing a plug of active drug in the middle of the unit. After the inert plugs have eroded, the drug is released, thus a lag-time occurs. Time of release can then be modulated by the length and composition of the plugs. The shells are made of slowly biodegradable polymer such as ethyl cellulose and a plasticizer such as cetostearyl alcohol is included35.
CodasTM (Chronotherapeutic Oral Drug Absorption System) technology: This is a multiparticle system designed for bedtime drug dosing, incorporating a 4–5-hour delay in drug delivery. This delay is introduced by the level of nonenteric release-controlling polymer applied to drug-loaded beads. The release-controlling polymer is a combination of water-soluble and water insoluble polymers35, 38. When fluid from the gastrointestinal tract comes into contact with the polymer-coated beads, the water-soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating. The water-insoluble polymer continues to act as a barrier, maintaining the controlled release of drug. The rate of release is essentially independent of pH, posture, and food38.
ContinTM technology: In this technology, the molecular coordination complexes are formed between a cellulose polymer and a nonpolar solid aliphatic alcohol optionally substituted with an aliphatic group by solvating the polymer with a volatile polar solvent and reacting the solvated cellulose polymer directly with the aliphatic alcohol, preferably as a melt. This constitutes the complex having utility as a matrix in controlled release formulations since it has a uniform porosity (ie semi permeable matrixes) that may be varied39.
GeoClockTM technology: It consists of a drug-free barrier layer on one or both bases of an active core (hydrophilic matrix). The partial coating modulates the core hydration process and reduces the surface area available for drug release. During the process of dissolution, the swellable barrier swells and gels, but is not eroded, thus acting as a modulating membrane during the release process. The erodible barrier will gradually be removed by the dissolution medium, hence, exposing in time an increasing extent of the planar surfaces of the core to interaction with the outer environment and so causing drug release40. Recently, this technology has been used to develop Lodotrat, a prednisone-containing chronopharmaceutical formulation for rheumatoid arthritis management. With this new ChDDs, the drug can be taken at bedtime, but the active substance only gets released in the early hours of the morning, the optimum time point to treat morning symptoms such as stiffness and pain due to the inhibition of inflammatory cytokines39.
The PortTM (Programmable Oral Release Technologies): This technology uses a unique coating to encapsulate the system that can provide multiple programmed release of drug. The basic design of the Port technology tablet consists of a polymer core matrix coated with a semi permeable, rate-controlling polymer. Poorly soluble drugs can be coated with proprietary solubilization agents to ensure uniform controlled release from the dosage form41. The basic design of the Port system of capsule consists of a hard gelatin capsule coated with a semi permeable, rate-controlling polymer. Inside the coated capsule is the osmotic energy source, which normally contains the therapeutic agent to be delivered. The capsule is sealed with a water-insoluble lipid separator plug. An immediate release dosage can be added above the plug to complete the dosing options41.
Three Dimensional Printing® (3DP) technology: This technique is used in the fabrication of complex oral dosage delivery pharmaceuticals based on solid free-form fabrication methods. It is possible to engineer devices with complicated internal geometries, varying densities, diffusivities, and chemicals42. Different types of complex oral drug delivery devices have been fabricated using the 3DP process: immediate–extended release tablets, pulse release, breakaway tablets, and dual pulsatory tablets. The enteric dual pulsatile tablets were constructed of one continuous enteric excipient phase into which diclofenac sodium was printed into two separated areas. These samples showed two pulses of release in vitro with a lag time between pulses of about 4 hours43. This technology is the basis of the TheriForm® technology. The latter is a micro fabrication process that works in a manner very similar to an ‘‘inkjet’’ printer. It is a fully integrated computer-aided development and manufacturing process. Products may be designed on a computer screen as three-dimensional models before actual implementation of their preparation process.
The TIMERx® technology: This technology is a very versatile hydrogel-based controlled release technology44. The unique nature of TIMERx intermolecular physical chemistry was described in relation to the technology’s potential to provide any one of a number of different release profiles, ranging from zero order to chronotherapeutic release. The authors claimed that the ‘‘molecular engine’’ replaces the need for complex processing or novel excipients and allows desired drug release profiles to be ‘‘factory set’’ following a simple formulation development process45. This technology combines xanthan and locust bean gums mixed with dextrose44. The physical interaction between these components works to form a strong binding gel in the presence of water. Drug release is controlled by the rate of fluid penetration from the GIT into the TIMERxTM gum matrix, which expands to form a gel and subsequently releases the active drug substance.
Some other controlled release systems that may find future applications in chronotherapy include erodible polymers in different forms46. Programmable pulsatile release capsule devices46, guar gum-based matrix tablets47, Sigmoidal release systems49-50 and self exploding micro particles51.
Compression coated tablets: These are dosage forms in which the core consists of tablet with an immediate-release compartment. It involves direct compression of both the core and the coat, avoiding the needs for separate coating process and use of coating solutions. The major disadvantages of the technique are that relatively large amounts of coating materials are needed and it is difficult to position the cores correctly for the coating process52. The core contains the drug and disintegration agent while the coat is made up of polymers such as hydroxyl propyl methylcellulose, hydroxyl ethyl cellulose or sodium alginate.
Futuristic prospect of ChrDDs
At present we have three classes of ChDDs as earlier mentioned (ie parenteral, oral and transdermal). It is believed that in the near future novel ChDDs will also be explored in the treatment or management of some ophthalmic other chronic and terminal disease conditions. One of such chronic disease conditions is glaucoma. Glaucoma is an increased in intraocular pressure (IOP), which can damage the optic nerve that transmits visual information to the brain. It has been reported that this IOP is high in the early hours in the morning at about 4.00am. Some drugs used in the treatment of glaucoma such as timolol or beta blockers can be designed into novel ChDDs with an appropriate polymer in the form of a tiny punctal plug. The plug can be so designed with the appropriate polymer to release the active drug at predetermined time to control high intraocular pressure associated with glaucoma in patients when inserted into a drainage channel in the eye. This ChDDs design will certainly address the problem with compliance among people who must use eye drops daily.
CONCLUSION:
Oral drug delivery is the largest, oldest, accurate and most preferred route of drug delivery. Sustained and controlled-release products provide a desired therapeutic effect, but they are not suitable for circadian disorders such as asthma, rheumatoid arthritis, and diabetics etc., which follow the biological rhythms. ChDDs can effectively solve this problem as it is modulated according to body's circadian clock giving release of drug after a predetermined lag time. A significant progress has been made toward achieving ChDDs that can effectively treat diseases with non-constant dosing therapies. Various ChDDs are currently researched and brought in the market, which surely assure a bright and promising future.
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Received on 12.07.2010 Modified on 23.07.2010
Accepted on 31.07.2010 © RJPT All right reserved
Research J. Pharm. and Tech. 4(2): February 2011; Page 197-202